Hypoxia inducible factor-1 alpha and prolinhydroxlase 2 polymorphisms in patients with severe sepsis: a prospective observational trial

Abstract

BackgroundHypoxia-inducible-factor-1α (HIF-1α) and HIF-1 degrading prolyl-hydroxylases (PHD) are key regulators of the hypoxic-inflammatory response. Functionally active genetic variants in the HIF-1α (C/T; Single Nucleotide Polymorphism (SNP) rs11549465) and the PHD2 gene (EGLN1; C/T; SNP rs516651 and T/C; SNP rs480902) are associated with altered HIF-1α mRNA nuclear translocation and an altered adaptation to hypoxia. Furthermore, the HIF system is important in surviving inflammatory disorders and sepsis. Thus, we tested the hypotheses, that SNPs in the HIF-1α or PHD2 genes are (1) common in Caucasians, with 2) the HIF-1α genetic variant being associated with an altered HIF-1α mRNA expression; and 3) independent risk factors for 30-day mortality in severe sepsis.MethodsAfter ethics approval, 128 septic patients (Caucasian descent) were included prospectively within 24 h after first diagnosing sepsis. Patients characteristics and severity of illness (simplified acute physiology score II), genotypes (Taqman assay), and their influence on leukocyte HIF-1α-mRNA-expression (Real-Time PCR) and 30-day mortality were determined.ResultsFrequencies were 0.8 % for homozygous HIF-1α TT-carriers (CT 17.6 %; CC 81.6 %), 2.5 % for homozygous PHD2 SNP rs516651 TT-allele carriers (CT 17.5 % and CC 80 %), and 9.4 % for homozygous PHD2 SNP rs480902 TT-allele carriers (CT 34.4 % and CC 56.3 %). While HIF-1α T-allele carriers had a borderline decrease in HIF-1α-mRNA-expression (p = 0.06) neither HIF-1α nor PHD2 SNPs were (independent) risk factors for 30-day mortality.ConclusionsGenetic variants in HIF-1α and PHD2 genes exist in Caucasians but do not appear to alter 30-day mortality in sepsis.

Hypoxic-Inflammatory Responses under Acute Hypoxia: In Vitro Experiments and Prospective Observational Expedition Trial

“…Cytokine concentrations were assessed from EDTA-plasma and cell culture supernatant using the Procarta multiplex cytokine kit (Affymetrix, Santa Clara, CA, USA) following the manufacturer's protocol as published previously [6,23]. In detail, plasma and supernatant concentrations of proinflammatory cytokines (Interleukin-3 (IL-3), Interleukin-6 (IL-6), tumor necrosis factor α (TNFα), anti-inflammatory cytokines (Interleukin-1 receptor antagonist (IL-1RA), Interleukin-10 (IL-10)), chemokines (chemokine C-C motif ligand 2/monocyte chemotactic protein 1 (CCL-2/MCP-1), C-X-C motif chemokine 12/stromal cell-derived factor 1 (CXCL-12/SDF-1α), and vascular endothelial growth factor A (VEGF-A) were measured at all four timepoints [55].…”

“…In this context, we have previously shown that additionally to the extent of hypoxic or inflammatory stimuli or their duration, genetic variants in HIF-1, HIF-2, and HIF-degrading PHD-2 alter human adaptation to hypoxia [15][16][17][18][19]. High altitude residents thus have blunted hypoxic ventilatory response and diminished pulmonary hypertension under hypoxia [20,21], increased heart rate, improved peripheral oxygen saturation, and reduced incidence of mountain sickness, as assessed using the Lake Louise Score (LLS) [15,16,[22][23][24]. LLS, which has recently been revised, is a well-established tool to evaluate the severity of acute mountain sickness (AMS) [25,26].…”

Immunometabolism and Sepsis: A Role for HIF?

“…Functionally active genetic variants in HIF-1 and PHD2 can impact on HIF-1α mRNA expression. However, they are not independent risk factors for 30-days mortality in severe sepsis (Höcker et al, 2015). A clinical trial investigating the potential of HIF-1 as a novel biomarker in septic shock has now been completed and data on the primary outcomes remains to be published (NCT02163473).…”

MAPK interacting serine/threonine kinase 1 ( MKNK1 ), one target gene of miR-223-3p, correlates with neutrophils in sepsis based on bioinformatic analysis

“…Similarly, Textoris et al have reported the independence of the expression of HIF-1 and outcomes of patients with sepsis [ 19 ]. Höcker and his coworkers have further announced that the expression of HIF-1α cannot alter 30-day mortality in severe sepsis [ 35 ].…”